Regulatory Affairs

 Abbreviation:
GATT- General Agreement on Tariffs and Trade
CAPA- Corrective and preventive action
CDER- Center for Drug Evaluation and Research
EMA- European Medicines Agency
ANDA- Abbreviated New Drug Application
PICS- Pharmaceutical Inspection Co-operation Scheme
TRIPS- Trade-Related Aspects of Intellectual Property Rights
CTD- Common Technical Document
WIPO- World Intellectual Property Organization
ICH- International Conference on Harmonization

 Definations:
Pharmacist Only Medicine: Pharmacist Only Medicines, are substances and
preparations for therapeutic use that –
 are substantially safe in use but require professional advice or counselling by a
pharmacist;
 require pharmacist advice, management, or monitoring;
Examples: Pseudoephedrine, Salbutamol

Prescription Only Medicine: Prescription only medicines, are substances and

preparations for therapeutic use that –
 require professional medical, dental, or veterinary management or
monitoring;
 are for ailments or symptoms that require professional medical, dental, or
veterinary diagnosis or management;
 may require further evaluation for safety or efficacy;
 cost of the drug is high, or when there is a risk of dependence
Examples: Amoxicillin, Cisplatin
 Poison: Must use distinctive packaging and strong warnings to display the
potential for:
 moderate to high toxicity;
 that may cause death or severe injury if ingested, inhaled, or in contact with
the skin or eyes.

Controlled Drug: Controlled Drugs, are substances and preparations for

therapeutic use which have high potential for abuse and addiction. The
possession of these medications without authority is an offence.
Examples: Amphetamine, Barbiturates

Biological Product: A biological product is a substance derived from a living

organism and used for the prevention or treatment of disease. Biologicals are
usually too complex for chemical synthesis by a laboratory.
Example: antitoxins, bacterial and viral vaccines, blood products.
Non-biological complex drugs/products: Non-biological Complex Drugs
are medical compounds that cannot be defined as small molecular, fully
identifiable drugs with active pharmaceutical ingredients. They are highly complex
and can not derived from living materials.
Example: polypeptides, liposomes.

 Objectives and Elements of the policy, NDP-2005

i. To ensure that the common people have easy access to useful, effective, safe and
good quality essential and other drugs at affordable prices.
ii. To strengthen the directorate of Drug Administration by raising its status.
iii. To update, from time to time, the criteria of registration for import of all systems of
medicines in line with the quality guidelines.
iv. To exercise government control over advertisement so that common people are not
hood-winked by commercial advertisement on Drugs and health matters.
v. To encourage all local and foreign companies to manufacture good quality essential
drugs in adequate quantities in the country.
 vi. To ban the manufacture, sale and distribution of counterfeit, adulterated and sub-
standard drugs and to award exemplary punishment to persons guilty of such
actions.
vii. To strengthen the system of procurement, storage and distribution of drugs and
medicines so that these are accessible to people in all areas of the country.
viii. To allow manufacturers to manufacture, distribute and sell drugs by their generic or
formulary names and trade or Brand names as appropriate for best identify of the
product.
ix. To continue the current system of controlling prices of the commonly used essential
drugs as listed and updated from time to time by the government.
x. To encourage both local and multinational manufacturers to establish full-fledged
research & Development facilities in the country.
xi. To encourage investors to set up facilities for manufacturing pharmaceutical raw
materials in the country.
xii. To ensure rational use of drugs by proper counseling and motivation of both the
prescribers and the end users.

 Strengthening of the Drug Regulatory Authority, NDP-2005

The following measures should be taken for the strengthening of the DRA-

i) The status of the directorate of drug administration (DGDA) should be raised to that of
the directorate general of drug administration with corresponding increase in its
manpower and infrastructure facilities.
ii) The organogram of the DGDA should accommodate all lawful systems of drug and
regulate them under unified control.
iii) The Regulatory responsibilities should be delegated to different directors under
DGDA to expedite and facilitate the functional process.
iv) The decision making process should be guided by the objective, non discriminatory
and transparent guideline and procedures.
v) The staff of DGDA should be adequately trained have clearly defined function and
powers and be entrusted with responsibility in relation to all aspects of registration,
manufacture, storage, distribution, sale ,import, export, and quality of drug in order to
ensure compliance with the laws, rule and regulations.
 Quality Assurance of Drugs and Pharmaceuticals, NDP-2005

One of the most important objectives of the NDP is to make good quality drugs available
at affordable prices. In order to achieve this objective, quality building in a drug at the
manufacturing stage by in process quality control and quality keeping in the drug in
transit and storage should be ensured by testing it at different stages before it reaches
the end-users.

i) Each Pharmaceutical company should have a quality control and quality assurance
system, which would monitor the entire process from the acquisition of raw material
to its conversion into a finished product.
ii) Each manufacturer should have a dedicated team of professionals for adequate
product and process design and statistical control of the process through in-process
and end-product testing.
iii) There should be documented Standard Operating Procedure based on WHO
recommended cGMP guidelines for manufacture of each product as well as for each
manufacturing unit process.
iv) All the unit process should be periodically validated to ensure correct end results.
The validation results should be properly documented.
v) Qualified professionals related to pharmaceutical sciences should be employed in all
the relevant departments, related to quality control and quality assurance.
vi) Quality of marketed drugs should be ensured by frequent post-marketing
surveillance by the Drug Inspectors and testing random samples of the marketed
drugs in the quality control laboratories.
vii) In addition to the QC laboratories of the companies there should be one Central
Drug Testing/ Quality Control Laboratory and a number of Regional Drug
Testing/Quality Control Laboratories.

 DRUG MANUFACTURING LICENSE

 REQUIREMENTS OF MANUFACTURING LICENSE APPROVAL

 Application to DGDA
 Form 12 and form 15 as per the schedule C and C (1) to Drug Rules 1946.
 New manufacturing License fees:
1. Biological: Tk. 30,000/-
2. Non-Biological: Tk. 15, 000/-
3. 15% VAT on both fees.
 Recipe Submission, if under process
 Updated Trade License
 List of Machineries and list of the Technical person with designation,
educational qualification, father’s name, permanent and present address.
 List of the reference book
 Organogram of the company
 Site master file
 Certificate from the Department of Environment
 Lay out plan of the Factory
 Copy of the project approval letter
 Recruitment letter, joining letter, educational certificate and affidavit of the
qualified personnel.
 List of the Directors/Entrepreneurs with father’s name, permanent and
present address.
 RECIPE APPROVAL
 PRODUCT REGISTRATION
 REQUIREMENTS PRODUCT REGISTRATION

Issuance of Registration Certificate

Registration certificate is issued for 05 (Five) years duration after satisfactory

evaluation of submitted document. After 05 (Five) years, registration certificate
can be renewed for further 05 (Five) years with submission and evaluation of
necessary documents.

Registration certificate must contain the following information

• Brand Name
• DAR number
• Issue Date
• Expiry Date
• Active ingredients with specification and quantity
 • Excipients with specification and quantity
• Authorized signatory

 DTL APPROVAL
 SAMPLE SUBMISSION FOR BP/USP PRODUCTS
Sample to be submitted from the first commercial batch within 7 days of
Manufacturing
 Application
 Photocopy of Annexure
 Certificate of Analysis
 Method of Analysis
  Calculation Sheet
 Working Standard
 UV-Spectophotometric Records

 TQM: Total quality management (TQM) as a term to describe an

organization's quality policy and procedure has fallen out of favor as
international standards for quality management have been developed.
Total quality management benefits and advantages:
 Strengthened competitive position
 Adaptability to changing or emerging market conditions and to environmental
and other government regulations
 Higher productivity
 Enhanced market image
 Elimination of defects and waste
 Reduced costs and better cost management
 Higher profitability
 Improved customer focus and satisfaction
 Increased customer loyalty and retention
 Increased job security
 Improved employee morale
 Enhanced shareholder and stakeholder value
 Improved and innovative processes

 ICH: ICH denotes for "International Conference on Harmonization of

Technical Requirements for Pharmaceuticals for Human Use is an initiative
that brings together regulatory authorities and pharmaceutical industry to
discuss scientific and technical aspects of pharmaceutical product
development and registration.

ICH Guidelines
The ICH may adopt a guideline in 1 of 4 categories:
1. Quality (Q) – addressing chemistry, manufacturing, and controls
 2. Safety (S) – addressing nonclinical studies
3. Efficacy (E) – addressing both clinical efficacy and safety studies
4. Multidisciplinary (M)

How are ICH Guidelines Composed and Harmonized?

To meet its mission of achieving harmonization, the ICH has an iterative process
to generate new guidelines. Both consist of the same 5 separate and clearly
defined steps.
Step 1: Consensus Building
In Step 1, the EWG prepares a draft of the full Technical Document based on the
objectives described in the Concept Paper. When the members of the EWG reach
consensus on the draft, the Technical Document is submitted to the ICH
Assembly.
Step 2: Draft Guideline
Step 2 is broken into 2 parts.
Step 2a occurs when the ICH Assembly agrees that the EWG has reached
consensus on the draft of the Technical Document.
Next, Step 2b consists of the Regulatory Members of the ICH Assembly revising
the draft Technical Guide Document as needed to develop a draft guideline, and
then providing their endorsement.

Step 3: Regulatory Consultation and Discussion

Step 3 is broken into 3 stages.
Stage I is the regional regulatory consultation, wherein the draft guideline is
subjected to regulatory review in ICH regions. During this stage, regulators may
provide comments to the ICH Secretariat for consideration.
After the comment period has ended, Stage II commences with the discussion of
the regional regulatory consultation comments by the EWG.
Once the EWG has addressed all of the comments and revised the draft guideline
(if needed), Stage III comprises the adoption of the revised draft guideline by the
Regulatory Members of the ICH Assembly.
Step 4: Adoption of an ICH Harmonized Guideline
During Step 4, the Regulatory Members of the ICH Assembly may agree that there
is adequate consensus on the Step 3 Expert Draft Guideline and adopt it as an ICH
Harmonized Guideline.
Step 5: Implementation
Immediately after adoption of the new or revised ICH Harmonized Guideline, Step
5 entails the regulatory implementation of the Guideline in accordance with the
national and local procedures of the ICH regions.

 Climate Zones for Stability Studies

Bangladesh is in the zone IVa.

Long term stability testing condition:

Climate zone Temperature Humidity Minimum duration

Zone IVa 30⁰C ± 2⁰ C 65% RH ± 5% RH 12 months

Accelerated and intermediate stability testing conditions:

 Six-System Inspection Model:
A model that can help pharmaceutical manufacturers comply with CGMP
regulations. The six systems referred to in this inspection model are: quality,
production, facilities and equipment, laboratory controls, materials, and
packaging and labeling.

 What are the criteria for a good CAPA?

Unfortunately, the FDA offers minimal guidance on selecting a CAPA system. At a
high level, the CAPA system must:
 Include CAPA procedures which address quality system requirements.
 Facilitate data analysis to identify the sources of product quality concerns.
 Enable organizations to monitor trends for preventive action.
 Integrate with surrounding systems and QA processes to assure data
quality.
 Facilitate statistical analysis and formal failure investigations.
 Allow organizations to validate the success of preventive or corrective
actions.

 Describe model of CTD with diagram

Module 1- Administrative Information and Prescribing Information
Relevant administrative documentation and the proposed label for use in
Bangladesh should be submitted in module 1 of the CTD dossier. This module
should be divided into the relevant sections, as described in Part B of this
document.
Module 2- Summary of the Dossier
Module 2 of the CTD dossier contains the summaries and overviews for the
quality, nonclinical, and clinical sections of the dossier (refer to ICH M4Q, M4S,
and M4E). The module begins with a general introduction to the medicine,
including its pharmacological class, mode of action, and proposed clinical use. The
summary of quality information should be provided according to WHO’s Quality
Overall Summary–product dossier (QOS-PD) template.
The clinical overview section should include a statement regarding good clinical
practice (GCP) compliance.

Module 3– Quality
Module 3 of the dossier contains the chemical, pharmaceutical, and biological
data relevant to the application. This information should be structured as
described in the Bangladesh CTD Module 2 (Quality Overall Summary) and 3
(Quality) guidelines. Also, refer to the ICH Guidelines M4Q (M4Q (R1): QUALITY
Module 2: Quality Overall Summary (QOS) and Module 3: Quality.

Module 4- Nonclinical Study Reports

Module 4 of the dossier contains the nonclinical (pharmacotoxicological) data
relevant to the application.
Exemptions apply to multisource (generic) products.

Module 5- Clinical Study Reports

Module 5 of the dossier contains the clinical data relevant to the application. In
most circumstances, the clinical studies included in module 5 of the dossier will
be international studies used to establish the pharmacodynamics,
pharmacokinetics, safety, and efficacy of the medicine across an international
patient population.

Schematic of the Organization of the ICH CTD:

 Objective of ICH

•To promote international harmonization of technical requirements to develop

safe, effective, and high quality medicines.

•To reduce the registration cost.

•To promote public health

•To prevent the duplication of clinical trials in Humans

•To minimize the animal use without compromising on the safety and quality of
drugs

 Phases of clinical trials in Cancer

Phase 0 clinical trials:

- The purpose of this phase is to help speed up and streamline the drug
approval process. Phase 0 studies may help researchers find out if the drugs do
what they’re expected to do. This may help save time and money that would
have been spent on later phase trials.
- Phase 0 studies use only a few small doses of a new drug in a few people. They
might test whether the drug reaches the tumor, how the drug acts in the
human body, and how cancer cells in the human body respond to the drug.
People in these studies might need extra tests such as biopsies, scans, and
blood samples as part of the process.
- Unlike other phases of clinical trials, there’s almost no chance the people in
phase 0 trials will benefit. The benefit will be for other people in the future.
And because drug doses are low, there’s also less risk to those in the trial.
- Phase 0 studies aren’t widely used, and there are some drugs for which they
wouldn’t be helpful. Phase 0 studies are very small, often with fewer than 15
people, and the drug is given only for a short time.
Phase I clinical trials:

- The first few people in the study get a very low dose of the treatment and are
watched very closely. If there are only minor side effects, the next few
participants get a higher dose. This process continues until doctors find a dose
that’s most likely to work while having an acceptable level of side effects.
- Phase I trials are also looking at what the drug does to the body and what the
body does with the drug.
- Safety is the main concern. The research team keeps a close eye on the people
and watches for any severe side effects. Because of the small numbers of
people in phase I studies, rare side effects may not be seen until later phases
of trials when more people receive the treatment.
- While some people may benefit from being on one, disease response is not the
main purpose of a phase I trial,
- Placebos (inactive treatments) are not used in phase I trials.
- Phase I trials usually include a small number of people (up to a few dozen).
- Phase I trials most often include people with different types of cancer.
- These studies are usually done in major cancer centers.

Phase II clinical trials:

- A group of 25 to 100 patients with the same type of cancer get the new
treatment in a phase II study. They’re treated using the dose and method
found to be the safest and most effective in phase I studies.
- Usually in a phase II clinical trials, everyone gets the same dose. But some
phase II studies randomly assign people to different treatment groups.
These groups may get different doses or get the treatment in different ways
to see which provides the best balance of safety and response.
- Placebos (inactive treatments) are not used in phase II trials.
- Phase II studies may be done at major cancer centers, community hospitals
or even doctors’ offices.
Phase III clinical trials:

- Most phase III clinical trials include a large number of patients, at least
several hundred.
- These studies are often done in many places across the country (or even
around the world) at the same time.
- Phase III clinical trials are more likely to be offered in local community
hospitals and doctor's offices.
- These studies tend to last longer than phase I and II studies.
- Placebos may be used in some phase III studies, but they’re never used
alone if there’s a treatment available that works. Sometimes, a patient who
is randomly assigned to the placebo for part of the study will at some point
be offered the standard treatment as well.

Phase IV clinical trials:

- Phase IV studies look at drugs that have already been approved by the FDA.
The drugs are available for doctors to prescribe for patients, but phase IV
studies might still be needed to answer important questions.
- These studies may involve thousands of people.
- This is often the safest type of clinical trial because the treatment has
already been studied a lot and has likely been given to many people. Phase
IV studies look at safety over time.
- These studies may also look at other aspects of the treatment, such as
quality of life or cost effectiveness.